Understanding DNA Damage Response (DDR)
Our DNA is constantly subjected to damage by ultraviolet light (UV) and this DNA damage accumulates in replicating cells, giving rise to mutations that can lead to premature aging, cancer, and other diseases. The two main toxic photoproducts that occur during UV skin exposure are cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproduct (6-4PPs) photolesions. CPDs are the major lesions that contribute to mutagenic events, and UV-induced carcinogenesis compared with 6-4PPs.
Normally, cells utilize a complex network SOS network called DNA damage response (DDR), which is responsible for detecting, repairing or stopping replication of damaged DNA cells. Individuals with XP either lack of the normal cellular repair mechanism or have defective repair pathways so that damage is not managed effectively.
Our lead drug development candidate, HB4208, is a DNA Damage Response (DDR) enzyme for topical treatment of the rare genetic disorder (orphan disease) Xeroderma Pigmentosum (XP). There is no cure or effective treatment for DNA damage in XP patients. HB4208 has shown positive results to modulate UV-induced DNA damage repair in animal model. The Company’s rare disease program is in early preclinical development.
Xeroderma Pigmentosum (XP)
Xeroderma Pigmentosum (XP) is a rare inherited skin disorder characterized by hypersensitivity to the sun and ultraviolet (UV) rays. Individuals with XP are highly susceptible to DNA damage caused by UV light phototoxicity due to either lack of the normal cellular repair mechanism or defective repair pathways to manage the damage. XP is a devastating disease for which there is no known cure and that significantly impacts both quality of life and life expectancy. Below are key points regarding XP*:
- Currently there are no FDA approved drugs for the treatment of XP.
- Standard treatment includes high levels of skin protection, including clothing and sun block, and individuals should avoid all UV / sun exposure whenever possible. This still does not prevent UV DNA damage lesions.
- Many children with XP develop their first case of skin cancer by the age of 10, some as early as four years of age.
- For XP patients younger than 20 years of age, the prevalence of skin cancer is almost 5,000 times greater than what would be expected in the general population. Removal of these skin cancers often leads to severe disfigurement.
- Nonmelanoma skin cancer risks may be increased by 150 percent when there is XP confirmed as a diagnosis.
- The risk of other cancers such as ocular and brain cancers also occurs.
- XP patients die young. The average lifespan for someone with XP is 29 – 37 years.
* Sources: https://www.aad.org/public/diseases/a-z/xeroderma-pigmentosum-sensitivity-to-sunlight ; https://medlineplus.gov/genetics/condition/xeroderma-pigmentosum/# ; https://rarediseases.org/rare-diseases/xeroderma-pigmentosum/ ; https://emedicine.medscape.com/article/1119902-overview ; https://link.springer.com/chapter/10.1007/978-981-10-6722-8_14